Chronic granulomatous disease (CGD) is a recessive genetic disorder in which phagocytes cannot generate superoxide and other reactive oxidants due to mutations in different subunits of the respiratory burst oxidase (NADPH-oxidase) complex. The clinical syndrome is characterized by recurrent, severe bacterial and fungal infections and chronic inflammation with granuloma formation. Mutations in the X-Iinked gene for gp91(phox), the larger subunit of the oxidase cytochrome b., account for the majority of cases of COD (X-CGD). A murine model of X-CGD has now been developed, based on the use of gene targeting to disrupt the X-linked gp91(phox) gene in murine embryonic stem cells. The phenotype of the X-CGD mouse, as manifested in the inbred C57BL/6 strain, will be studied in this proposal. The frequency of spontaneous infectious and granulomatous complications in a specific pathogen free environment will be monitored, and the relative susceptibility of X-CGD mice to catalase-positive and catalase-negative microbes will be determined in experimental pneumonia and peritonitis. Other experiments will address the hypotheses that phagoycte-generated oxygen radicals are both important mediators of inflammatory tissue injury and at the same time essential for normal resolution of the inflammatory process. Acute and chronic injury will be induced in the skin or lung using either bacteria or non-infectious agents. The natural history of the inflammatory lesion will be compared between X-CGD and wild type mice. In some experiments, mice with a combined genetic deficiency of both the respiratory burst and neutrophil neutral proteases (bg/bg) will also be studied. Evaluation of the host response will include assessment of tissue injury by histologic analysis and by quantitation of edema formation, and characterization of the inflammatory cell infiltrate using histologic, morphometric, and immunohistochemical techniques. Experimental conditions which induce chronic foci of inflammation in X-CGD mice will be determined, and the efficacy of dexamethasone and interferon-gamma in ameliorating this process will be examined. This studies should provide new insight into the pathogenesis and treatment of CGD, and serve as a foundation for future investigations of these mice, including the impact of gene replacement therapy and the interaction of the X-CGD allele with other genetic defects influencing the inflammatory response. More broadly, the experiments described in this proposal should contribute to knowledge of the role of phagocyte oxidant production in acute and chronic inflammation in other clinical settings, and may suggest new approaches to treatment of these disorders.